Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China; Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China; Thalassemia Diagnosis Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
Medical Genetic Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China; Maternal and Children Metabolic-Genetic Key Laboratory, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China; Thalassemia Diagnosis Center, Guangdong Women and Children Hospital, Guangzhou, Guangdong 510010, China.
Clin Biochem. 2020 Feb;76:11-16. doi: 10.1016/j.clinbiochem.2019.11.003. Epub 2019 Nov 22.
The clinical and hematologic features of thalassemia are due to different factors, and patients with identical genotypes may regularly exhibit variable severity. In the present work, one homozygous Chinese γ(γδβ)-thalassemia case with an asymptomatic phenotype, which is contrary to traditional views, was identified. Analysis of the underlying causes of this rare clinical phenotype involved accurate genetic diagnosis and detection of several genetic modifications.
Six members of the proband's family were enrolled in the study. Hematological parameters and hemoglobin analysis results were recorded. A suspension-array system, multiplex gap-polymerase chain reaction (gap-PCR) and multiplex ligation-dependent probe amplification (MLPA) were used together to characterize genotypes. Sanger sequencing was utilized to examine the KLF1 gene and four primary fetal hemoglobin (Hb F)-associated single-nucleotide polymorphisms (SNPs).
Four family members carried the Chinese γ(γδβ)-thalassemia mutation, and a homozygous state was ultimately diagnosed for the proband. All of the Chinese γ(γδβ) mutation-positive cases were coinherited with the Southern Asian α-thalassemia deletion (- - /αα). Two SNP variants, rs7776054 and rs9399137, in the HBS1L-MYB locus were detected in the proband.
Thus far, this is the first study to describe the molecular characterization of a homozygous Chinese γ(γδβ)-thalassemia patient who exhibits no clinical symptoms. Our findings suggest that coinheritance of α-thalassemia or HBS1L-MYB locus variants may affect the clinical severity of Chinese γ(γδβ)-thalassemia. We conclude that the molecular examination of genetic determinants known to be associated with clinical outcomes in Chinese γ(γδβ)-thalassemia should be emphasized.
地中海贫血的临床和血液学特征是由不同的因素引起的，具有相同基因型的患者可能会定期表现出不同的严重程度。本研究鉴定了一例同合子中国γ(γδβ)-地中海贫血病例，其临床表现为无症状表型，与传统观点相反。对这种罕见临床表型的潜在原因的分析涉及准确的基因诊断和几种基因修饰的检测。
研究纳入了先证者的 6 名家庭成员。记录了血液学参数和血红蛋白分析结果。使用悬浮液芯片系统、多重 gap-聚合酶链反应（gap-PCR）和多重连接依赖性探针扩增（MLPA）联合对基因型进行特征分析。利用 Sanger 测序检测 KLF1 基因和四个主要胎儿血红蛋白（Hb F）相关的单核苷酸多态性（SNP）。
有 4 名家庭成员携带中国γ(γδβ)-地中海贫血突变，最终诊断先证者为纯合子状态。所有中国γ(γδβ)突变阳性病例均与南亚α-地中海贫血缺失（--/αα）共同遗传。在先证者中检测到 HBS1L-MYB 基因座的两个 SNP 变体 rs7776054 和 rs9399137。
迄今为止，这是首次描述无临床症状的纯合子中国γ(γδβ)-地中海贫血患者的分子特征。我们的研究结果表明，α-地中海贫血或 HBS1L-MYB 基因座变异的共同遗传可能影响中国γ(γδβ)-地中海贫血的临床严重程度。我们得出结论，应该强调对与中国γ(γδβ)-地中海贫血临床结局相关的遗传决定因素的分子检查。
